US9688750B2 - Anti-nodal antibodies and methods of using same - Google Patents

Anti-nodal antibodies and methods of using same Download PDF

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US9688750B2
US9688750B2 US14/877,617 US201514877617A US9688750B2 US 9688750 B2 US9688750 B2 US 9688750B2 US 201514877617 A US201514877617 A US 201514877617A US 9688750 B2 US9688750 B2 US 9688750B2
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nodal
antibody
antibodies
cells
cancer
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US20160130335A1 (en
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Menotti Ruvo
Annamaria Sandomenico
Antonio Leonardi
Luca Sanguigno
Mary J. C. Hendrix
Elisabeth A. Seftor
Richard E. B. Seftor
Luigi Strizzi
Zhila Khalkhali-Ellis
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Ann and Robert H Lurie Childrens Hospital of Chicago
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Ann and Robert H Lurie Childrens Hospital of Chicago
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    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/22—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against growth factors ; against growth regulators
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Definitions

  • Nodal is a highly conserved morphogen belonging to the transforming growth factor beta (TGF ⁇ ) super family (Schier et al., 2003, Annu Rev. Cell Dev. Biol. 19:589-621). By acting as an organizing signal before gastrulation, Nodal initiates embryonic axis formation, and previous studies demonstrated that the ectopic expression of Nodal induces mesendodermal fates in ectopic positions (Whitman, 2001, Dev. Cell 1:605-617; Schier, 2003, Annu Rev. Cell Dev. Biol. 19:589-621; Iannaccone et al., 1992, Dev. Dyn.
  • TGF ⁇ transforming growth factor beta
  • a monoclonal antibody that binds to Nodal comprises an HVR-H1 comprising the amino acid sequence of SEQ ID NO:7; an HVR-L1 comprising the amino acid sequence of SEQ ID NO:4; an HVR-L2 comprising the amino acid sequence of SEQ ID NO:5; and an HVR-L3 comprising the amino acid sequence of SEQ ID NO:6.
  • the antibody further comprises at least one human framework region.
  • the human framework region comprises a human VH Acceptor 2 framework.
  • human framework region comprises a human VL kappa subgroup I consensus framework.
  • the invention also provides isolated nucleic acid encoding a monoclonal antibody that specifically binds to Nodal, wherein the antibody specifically binds to an epitope in SEQ ID NO:13, and wherein the antibody inhibits Nodal activity.
  • the antibody comprises a VH chain region comprising CDR-H1 of SEQ ID NO:7, CDR-H2 of SEQ ID NO:8, and CDR-H3 of SEQ ID NO:9, and a VL chain region comprising CDR-L1 of SEQ ID NO:4, CDR-L2 of SEQ ID NO:5, and CDR-L3 of SEQ ID NO:6.
  • the VH chain region comprises SEQ ID NO:2 and the VL chain region comprises SEQ ID NO:1.
  • the invention also provides isolated nucleic acid encoding a monoclonal antibody that specifically binds to Nodal, wherein the antibody specifically binds to an epitope in SEQ ID NO:13, and wherein the antibody inhibits Nodal activity.
  • the antibody comprises the VL chain region comprises CDR-L1 of SEQ ID NO:4, CDR-L2 of SEQ ID NO:5, and CDR-L3 of SEQ ID NO:6.
  • the VL chain region comprises SEQ ID NO:1.
  • the antibody is a humanized form of a monoclonal antibody comprising the VH chain region of SEQ ID NO:2 and the VL chain region of SEQ ID NO:1.
  • the antibody inhibits Nodal binding to Cripto-1.
  • the antibody inhibits Nodal binding to the Alk4/7/ActRIIB receptor complex
  • FIG. 21 shows that nonaggressive, Nodal-negative C81-61 melanoma cells are tumorigenic after transfection with Nodal cDNA
  • FIG. 52 shows overlay plots of SPR sensorgrams showing the binding of hNodal(44-56) with both the 3D1 mAb (a) and its Fab′ fragment (b) immobilized on a CM5 sensor chip.
  • the interaction was monitored at concentrations of peptide ranging between 0.5 and 20 ⁇ M for 3D1 and between 1 and 20 ⁇ M for the Fab′ fragment, obtaining dose-dependent binding curves.
  • numbering of immunoglobulin amino acid residues is done according to the immunoglobulin amino acid residue numbering system of Kabat, et al., unless otherwise indicated.
  • the residues that make up these six CDRs have been characterized by Kabat as follows: residues 24-34 (CDRL1), 50-56 (CDRL2) and 89-97 (CDRL3) in the light chain variable region and 31-35 (CDRH1), 50-65 (CDRH2) and 95-102 (CDRH3) in the heavy chain variable region; Kabat et al., (1991) Sequences of Proteins of Immunological Interest, 5th Ed.
  • fully human framework means a framework with an amino acid sequence found naturally in humans.
  • fully human frameworks include, but are not limited to, KOL, NEWM, REI, EU, TUR, TEI, LAY and POM (See, e.g., Kabat et al., (1991) Sequences of Proteins of Immunological Interest, US Department of Health and Human Services, NIH, USA; and Wu et al., (1970) J. Exp. Med. 132, 211-250, both of which are herein incorporated by reference).
  • humanized antibodies of the present invention have fully human frameworks, or frameworks with one or more amino acids changed (e.g., to accommodate CDRs of the invention).
  • Such antibodies may be of any immunoglobulin class including IgG, IgM, IgE, IgA, and any subclass thereof.
  • a hybridoma producing a mAb of the present invention may be cultivated in vitro, in situ or in vivo.
  • Chimeric antibodies are molecules—different portions of which are derived from different animal species, such as those having variable region derived from a murine mAb and a human immunoglobulin constant region, which are primarily used to reduce immunogenicity in application and to increase yields in production, for example, where murine mAbs have higher yields from hybridomas but higher immunogenicity in humans, such that human/murine chimeric mAbs are used.
  • Chimeric antibodies and methods for their production are known in the art (Cabilly et al., Proc. Natl. Acad. Sci. USA 81:3273-3277 (1984); Morrison et al., Proc. Natl. Acad. Sci.
  • group refers to a group of patients as well as a sub-group of patients.
  • the terms “cell,” “cell line,” and “cell culture” include progeny. It is also understood that all progeny may not be precisely identical in DNA content, due to deliberate or inadvertent mutations. Variant progeny that have the same function or biological property, as screened for in the originally transformed cell, are included.
  • the “host cells” used in the present invention generally are prokaryotic or eukaryotic hosts.
  • overexpression of Nodal protein and “aberrant expression of Nodal protein” are intended to indicate a reactivation of the embryonic Nodal signaling pathway or an abnormal level of expression of the Nodal protein in a cell (e.g., within a cancer or tumor or other disease process in which Nodal is elevated) within a specific tissue or organ of a patient relative to the level of expression in a normal cell from that tissue or organ.
  • patients having a cancer characterized by overexpression or aberrant expression of Nodal can be determined by standard assays known in the art.
  • Overexpression or aberrant expression can be measured in fixed cells of frozen or paraffin-embedded tissue sections using immunohistochemical (IHC) detection. When coupled with histological staining, localization of the targeted protein can be determined and extent of its expression (e.g., within a tumor) can be measured both qualitatively and semi-quantitatively.
  • IHC immunohistochemical
  • carcinoma including that of the bladder (including accelerated and metastatic bladder cancer), breast, colon (including colorectal cancer), kidney, liver, lung (including small and non-small cell lung cancer and lung adenocarcinoma), ovary, prostate, testes, genitourinary tract, lymphatic system, rectum, larynx, pancreas (including exocrine pancreatic carcinoma), esophagus, stomach, gall bladder, cervix, thyroid, and skin (including squamous cell carcinoma); hematopoietic tumors of lymphoid lineage including leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkins lymphoma, non-Hodgkins lymphoma, hairy cell lymphoma, histiocytic lymph
  • the therapeutic antibodies or compositions of the invention may be desirable to administer the therapeutic antibodies or compositions of the invention locally to the area in need of treatment; this may be achieved by, for example, local infusion, topical application, by injection, by means of a catheter, by means of a suppository, or by means of an implant, said implant being of a porous, non-porous, or gelatinous material, including membranes or fibers.
  • antibodies are delivered in a controlled release system.
  • Exemplary buffering agents include both organic and inorganic acids and salts thereof such as citrate buffers (e.g., monosodium citrate-disodium citrate mixture, citric acid-trisodium citrate mixture, citric acid-monosodium citrate mixture, etc.), succinate buffers (e.g., succinic acid-monosodium succinate mixture, succinic acid-sodium hydroxide mixture, succinic acid-disodium succinate mixture, etc.), tartrate buffers (e.g., tartaric acid-sodium tartrate mixture, tartaric acid-potassium tartrate mixture, tartaric acid-sodium hydroxide mixture, etc.), fumarate buffers (e.g., fumaric acid-monosodium fumarate mixture, etc.), fumarate buffers (e.g., fumaric acid-monosodium fumarate mixture, etc.), fumarate buffers (e.g., fumaric acid-monosodium
  • stabilizers may be used, for example, polhydric sugar alcohols, preferably trihydric or higher sugar alcohols, such as glycerin, erythritol, arabitol, xylitol, sorbitol and mannitol.
  • Stabilizers refer to a broad category of excipients which can range in function from a bulking agent to an additive which solubilizes the therapeutic agent or helps to prevent denaturation or adherence to the container wall.
  • Such antibodies may be of any immunoglobulin class including IgG, IgM, IgE, IgA, IgD and any subclass thereof.
  • the hybridoma producing monoclonal antibody of the invention may be cultivated in vitro or in vivo. Accordingly, in one embodiment, the invention also provides various cell lines (e.g., immortalized B cell lines) that produce anti-Nodal antibody of the invention.
  • Chimeric antibodies can be constructed as disclosed in WO 93/03151. Binding proteins which are derived from immunoglobulins and which are multivalent and multispecific, such as the “diabodies” described in WO 94/13804, also can be prepared. Antibodies can be purified by methods well known in the art. For example, antibodies can be affinity purified by passage over a column to which the relevant antigen is bound. The bound antibodies can then be eluted from the column using a buffer with a high salt concentration.
  • F(ab′) 2 fragments contain the variable region, the light chain constant region and the CH1 domain of the heavy chain. However, these fragments can now be produced directly by recombinant host cells.
  • the antibody fragments can be isolated from an antibody phage library.
  • F(ab′) 2 -SH fragments can be directly recovered from E. coli and chemically coupled to form F(ab′) 2 fragments (Carter, et al., Bio/Technology 10:163 (1992).
  • F(ab′) 2 fragments can be isolated directly from recombinant host cell culture. Other techniques for the production of antibody fragments will be apparent to the skilled practitioner.
  • heteroconjugate antibodies can be utilized in the present invention.
  • Heteroconjugate antibodies are composed of two covalently joined antibodies. Such antibodies have, for example, been proposed to target immune system cells to unwanted cells (U.S. Pat. No. 4,676,980).
  • a method of characterizing or diagnosis a subject comprising administering to a subject/patient (e.g., a subject having or suspected of having cancer) an amount of anti-Nodal antibody effective to bind Nodal and monitoring the subject following the administering after a particular time (e.g., minutes, hours, days) sufficient to permit the anti-Nodal antibody to bind sites within the subject that express Nodal.
  • a particular time e.g., minutes, hours, days
  • the time permits unbound Nodal to be cleared from the subject (e.g., so as to reduce and/or eliminate background signal).
  • the anti-Nodal antibody is labeled.
  • the background anti-Nodal antibody level is determined.
  • FIG. 3 shows hybridoma clones comparatively screened by ELISA to identify those secreting monoclonal antibodies (mAbs) selectively recognizing E49E50 residues of the Nodal pre-helix loop region. Monoclonal antibodies (mAbs) selectively recognizing the wild type peptide were selected for further investigation.
  • Mel-2 Human embryonic stem cell line
  • H1 Human embryonic stem cell line
  • H9 Human embryonic stem cell line
  • C8161 Aggressive human melanoma cell line
  • Melanocyte Normal human pigmented cell line
  • MDA-MB-231 Aggressive human breast carcinoma cell line
  • Hs578 Bst Normal human breast cell line
  • HMEpC Normal human breast epithelial cell line.
  • This method can be used for live cell sorting using FACS; Sorted tumor cells analyzed by RT-PCR for gene expression; Western blot for protein expression; for clonogenic potential in soft agar; and for tumorigenic potential in vivo. Confocal microscopy can be performed for image analysis of Nodal mRNA together with CD133, another stem cell marker.
  • Size-exclusion chromatography purifications were performed on a SuperdexTM 200 HR 10/300 (GE Healthcare, Piscataway, N.J., USA) gel filtration column, using PBS pH 7.4 as running buffer, at a constant flow rate of 0.5 mL/min, with an elution volume of 25 mL and monitoring the absorbance at 280 nm.
  • the following antibodies were used for WB: rabbit anti-Nodal (H-110; Santa Cruz Biotechnology, Dallas Tex.); rabbit anti-P-Smad2 (44-244G; Life Technologies, Grand Island, N.Y.); rabbit anti-Smad2/3 (07-408; Millipore, Lake Placid, N.Y.); rabbit anti-P-p44/42 MAPK (P-ERK1/2) (9101S; Cell Signaling, Beverley, Mass.); rabbit anti-p44/24 MAPK (ERK1/2) (44-654-G; Life Technologies); mouse anti-actin (MAB1501; Millipore, Temecula, Calif.).
  • C8161 melanoma cells (5,000 cells/well) were suspended in 0.35% agarose, RPMI 1640; 10% serum with of either 4 ⁇ g/ml mouse IgG control (Jackson ImmunoResearch, West Groove, Pa.) or 3D1 mAb (2.8 ⁇ g/ml) and were then overlayed onto a solidified layer of 0.5% agar; RPMI 1640; 10% serum in 6-well dishes. Cell clusters were allowed to form and were scored (50 cells or larger clusters) after 3 weeks in culture. Triplicate wells were averaged from separate experiments and presented as a percentage (mean ⁇ SEM) of IgG control.

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US10494428B2 (en) 2014-10-07 2019-12-03 Ann & Robert H. Lurie Children's Hosp. of Chicago Anti-nodal antibodies and methods of using same
US10508147B2 (en) 2014-10-07 2019-12-17 Ann & Robert H. Lurie Children's Hospital Anti-nodal antibodies and methods of using same
US11331019B2 (en) 2017-08-07 2022-05-17 The Research Foundation For The State University Of New York Nanoparticle sensor having a nanofibrous membrane scaffold
WO2019236769A1 (en) * 2018-06-05 2019-12-12 University Of Mississippi Medical Center Production of sized macro- and micro- elp particles for drug delivery
EP4574176A3 (de) * 2018-06-05 2025-09-17 University of Mississippi Medical Center Herstellung von makro- und mikro-elp-partikeln zur arzneimittelabgabe

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